Treatment of dry skin

ABSTRACT

Preventive as well as therapeutic treatment to alleviate the symptoms of disorders characterized by cracking, flaking or scaling of the skin consisting of the topical application of a lotion, cream or ointment containing one or more of the α- or β-hydroxy acids or α-keto acids and esters thereof, their amides and their ammonium salts is disclosed. The compounds include free acid, amide and/or ammonium salt forms of citric acid, glycolic acid, glucuronic acid, galacturonic acid, glucuronolactone, gluconolactone, α-hydroxybutyric acid, α-hydroxyisobutyric acid, lactic acid, malic acid, mandelic acid, mucic acid, pyruvic acid, methyl pyruvate, ethyl pyruvate, β-phenyllactic acid, β-phenylpyruvic acid, saccharic acid, tartaric acid, tartronic acid, and β-hydroxybutyric acid. The therapeutic composition may include one or more of the compounds present in the total amount of from one to twenty percent. Topical application to affected areas has been found to achieve amelioration of the dry skin.

This is a division of application Ser. No. 720,835 filed Sept. 7, 1976now U.S. Pat. No. 4,105,783, which is a continuation-in-part of ourcopending patent application Ser. No. 598,224, filed July 23, 1975, nowU.S. Pat. No. 4,021,572, hereby incorporated by reference, and isrelated to our copending applications Ser. Nos. 556,423 and 556,424,filed Mar. 7, 1975, now U.S. Pat. Nos. 3,988,470 and 3,984,566,respectively, which are divisions of application Ser. No. 445,231, filedFeb. 25, 1974, now U.S. Pat. No. 3,920,835, which in turn was acontinuation-in-part of application Ser. No. 394,269, filed Sept. 4,1973, now U.S. Pat. No. 3,879,537.

This invention relates to a treatment for skin disorders characterizedby cracking, flaking or scaling of hands, feet or the body commonlyknown as "dry skin," and specifically to compounds which have been foundto be effective when topically applied to prevent as well as heal theskin lesions associated with these conditions in humans.

Severe "dry skin" conditions known as ichthyosis are hereditarydisorders. The term ichthyosis alludes to a fish scale-like appearanceof the human skin. Ichthyosis, characterized by a "dry skin" appearance,is usually detected during the early years of childhood. Small, finescales with a "pasted-on" appearance are found most prominently on thetrunk and upper extremities. Larger, more adherent scales are present onthe legs. Only a small number of the population are affected by thishereditary disorder.

In contrast to ichthyosis, mild to moderate "dry skin" conditions arequite common among the population. These common "dry skin" conditionsare specially pronounced during the fall and winter seasons, whenenvironmental humidity is comparatively low. They are characterized byfissures, chaps, cracks or flakes of the skin on hands, face, neck andlegs.

Conventional treatments for all kinds of dry skin conditions primarilyinvolve the topical application of oils or oil preparations, andhydrating emollients. In addition, ointments containing salicylic acid,urea, glycerol, propylene glycol, sorbitol or vitamin A have been used.Prior treatments, however, have not been universally successful, andhave, in many cases, been unable to promote healing to cause a completeremission of the symptoms. Because the mechanisms involved in causingdry skin are not known, treatment has usually resulted in a temporaryremission or healing of the flaky or scaly lesions.

We have now discovered that "dry skin" conditions may be successfullyprevented or treated with the acid, amide or ammonium salt of α- orβ-hydroxyacids or α-keto acids and esters thereof. The compounds of thepresent invention include citric acid, glycolic acid, glucuronic acid,galacturonic acid, glucuronolactone, gluconolactone, α-hydroxybutyricacid, α-hydroxyisobutyric acid, lactic acid, malic acid, mandelic acid,mucic acid, pyruvic acid, methylpyruvate, ethyl pyruvate, β-phenylacticacid, β-phenylpyruvic acid, saccharic acid, tartaric acid, tartronicacid, and β-hydroxybutyric acid. Generally, the amide may be formed fromacid anhydride or lactone and ammonia or any organic primary orsecondary amine. The ammonium salt may be formed directly from acid andan organic primary, secondary or tertiary amine.

Preferred organic primary amines include any alkylamines such asmethylamine and ethylamine; ethanolamines such as monoethanolamine andmonoisopropanolamine; and diamines such as ethylenediamine and1,2-diaminopropane.

Preferred organic secondary amines include dialkylamines such asdimethylamine and diethylamine; diethanolamine and diisopropanolamine;N-methylethanolamine and N-ethylethanolamine.

Preferred organic tertiary amines include trialkylamines such astrimethylamine and triethylamine; triethanolamine;N-methyldiethanolamine and triisopropanolamine.

It has been established through tests on humans having "dry skin"conditions that topical application of a lotion, cream or ointmentcontaining from 1 to 20 percent of at least one acid, the ester or theamide or the ammonium salt of the present invention and preferably from2 to 10 percent thereof, is therapeutically effective, when applied on adaily basis, to cause, within about one to two weeks, a return of theaffected areas to a normal skin condition. If two or more acids, amidesor ammonium salts are used in a composition of the invention, the totalconcentration of the compounds is preferred not to exceed 10 percent byweight of the composition. It has also been found in humans havingfrequent occurrence of cracking or flaking skin that topical applicationof the aforementioned composition of the present invention is effective,when applied on a daily basis, in preventing development of dry skinlesions.

Accordingly, it is the object of this invention to provide a cosmeticcomposition containing at least one of the acids, the amides and/or theammonium salts, which when topically applied will reliably prevent thedevelopment of dry skin conditions.

It is another object of this invention to provide a medicinalcomposition containing at least one of the acids, the amides and/or theammonium salts which when topically applied will substantially alleviatethe symptoms of dry skin.

It is still another object to provide a method for treating dry skinwith a nonirritant and nontoxic lotion, cream or ointment of the presentinvention.

It is still another object to provide a safe and efficient method fortreating the symptoms of dry skin through regular topical application ofa medicinal composition which will promote healing within about one totwo weeks.

It is still another object of this invention to provide a method forformulating a cosmetic as well as medicinal composition in lotion, creamor ointment which when topically applied at least daily to skin areasprone to lesions of cracking, flaking or scaling will prevent indevelopment of dry skin or result in a restoration of normal healthyskin condition.

PREPARATION OF THE THERAPEUTIC COMPOSITIONS

Previously, in treatment of extremely dry skin conditions such asichthyosis, α- or β-hydroxyacids or α-ketoacids were prepared in acomposition containing 5 to 10 percent by weight of the compounds in acream or ointment. The pH of the composition was about 2 or less. Intreatment of common dry skin conditions according to this invention wefound that the above composition with low pH could cause some skinirritation (redness and sensation of burning) on some of the sensitivesubjects. It was therefore desirable to develop compositions which weretherapeutically effective but not irritative.

Most inorganic alkalis, forming inorganic salts with α- orβ-hydroxyacids or α-ketoacids that do not readily penetrate human skin,cannot be used to neutralize these acids. It has previously beendiscovered that certain organic bases, and ammonium hydroxide, may besuccessfully used to raise the pH of the compositions containing α- orβ-hydroxy acids or α-ketoacids without compromising the therapeuticefficaciousness of the active ingredients. Under such conditions theactive ingredients are in the form of amide or ammonium salt. Theorganic bases may include any organic amine of primary, secondary ortertiary family. The organic primary amines may include any alkylaminessuch as methylamine and ethylamine; any ethanolamines such asmonoethanolamine and monoisopropanolamine; any diamines such asethylenediamine and 1,2-diaminopropane. The organic secondary amines mayinclude dialkylamines such as dimethylamine and diethylamine;diethanolamine and diisopropanolamine; N-methylethanolamine andN-ethylethanolamine. The organic tertiary amines may includetrialkylamines such as trimethylamine and triethylamine;triethanolamine; N-methyldiethanolamine and triisopropanolamine.

The α and β-hydroxyacids, α-ketoacids and the esters of the presentinvention include citric acid, glycolic acid, glucuronic acid,galacturonic acid, glucuronolactone, gluconolactone, α-hydroxybutyricacid, α-hydroxyisobutyric acid, lactic acid, malic acid, mandelic acid,mucic acid, pyruvic acid, methyl pyruvate, ethyl pyruvate;β-phenyllactic acid, β-phenylpyruvic acid, saccharic acid, tartaricacid, tartronic acid and β-hydroxybutyric acid.

Generally, a nonirritating composition of this invention should have apH of the lotion, cream or ointment between 3.5 and 7.5.

To prepare an amide or an ammonium salt of the present invention thelactone or the hydroxyacid or the ketoacid is allowed to react at roomtemperature with ammonium hydroxide or an organic amine in aqueous oralcoholic aqueous solution. Generally, the amide or ammonium salt thusformed needs no isolation procedure and may be directly incorporatedinto the therapeutic composition.

The initial concentration of α or β-hydroxyacid or α-ketoacid may rangefrom 1 to 20 percent by weight of the total composition. The preferredconcentration range, however, is from 2 to 10 percent.

Ordinary distilled water may be used as a solvent in the preparation ofthe composition. The concentration of the solvent may range from 5 to 30percent by volume of the total composition.

In a variety of methods for formulating a composition of the presentinvention two or more than two different amides or ammonium salts mayalso be utilized in the composition.

The prophylactic as well as therapeutic composition may be prepared in aform of lotion, cream or ointment. In these instances, cosmeticallyacceptable ingredients are incorporated into the formulation, andlotions, creams or ointments are readily prepared.

The following are illustrative examples of formulations of compositionsaccording to this invention. Although the examples utilize only selectedformulations useful according to this invention, it should be understoodthat the following examples are illustrative and not limited. Therefore,any of the aforementioned acids, esters and amines may be substitutedaccording to the teachings of this invention in the followingformulations.

EXAMPLE 1

Glycolic acid, 5 grams was dissolved in 10 ml water and ethanolamine, 3ml was added to partially neutralize the acidity of the solution. Thissolution was admixed with 82 grams of water-nonwashable lotion preparedfrom mineral oil, cottonseed oil, isopropyl palmitate and water with asurfactant such as sorbitan sesquioleate. The ingredients of said lotionare present in 15:15:5:60:5 parts by weight, respectively. The lotionthus prepared is stored in a plastic squeeze bottle having a nozzleattached thereto.

EXAMPLE 2

Lactic acid, USP grade 5 ml was dissolved in 10 ml of water andtriethanolamine, 5 ml was added to neutralize partially the acidity ofthe solution. This solution was admixed with 80 grams ofwater-nonwashable lotion prepared from mineral oil, cottonseed oil andwater with a surfactant such as sorbitan sesquioleate. The ingredientsof said lotion are present in 30:15:50:5 parts by weight respectively.

EXAMPLE 3

    ______________________________________                                        Part A:   Polyoxyethylene (20) sorbitan                                                 monooleate (hereinater Tween 80)                                                                     5 gm                                                   Cetyl alcohol         20 gm                                         Part B:   Water                 45 ml                                                   Propylene glycol      10 ml                                                   Glycolic acid         10 gm                                                   Ethanolamine           7 ml                                         ______________________________________                                    

Heat Part A to 75° C. and heat Part B to 75° C. Add Part B slowly toPart A with agitation. Continue agitation until the mixture iscongealed. The water-washable cream thus prepared has a pH of 4.7.

EXAMPLE 4

    ______________________________________                                        Part A:   Tween 80               5 gm                                                   Cetyl alcohol         22 gm                                         Part B:   Water                 55 ml                                                   Propylene glycol      10 ml                                                   Lactic acid            5 ml                                                   Ethanolamine           2 ml                                         ______________________________________                                    

Heat Part A to 75° C. and heat Part B to 75° C. Add Part B slowly toPart A with agitation. Continue agitation until the mixture iscongealed. The water-washable cream thus prepared has a pH of 4.5.

EXAMPLE 5

    ______________________________________                                        Part A:   Tween 80              5     gm                                                Cetyl alcohol         15    gm                                                Stearyl alcohol       5     gm                                      Part B:   Water                 60    ml                                                Propylene glycol      5     ml                                                Citric acid           2     gm                                                Lactic acid           2     ml                                                Glycolic acid         2     gm                                                Ethanolamine          3     ml                                      ______________________________________                                    

Heat both Part A and Part B to 75° C. Add Part B slowly to Part A withagitation. Continue agitation until the mixture is congealed. Thewater-washable cream containing three active ingredients has a pH of4.4.

EXAMPLE 6

Glycolic acid, 7 grams was dissolved in 10 ml of ice water andethanolamine, 5 ml was added to neutralize partially the acidity of thesolution. This solution was admixed with 78 grams of water-nonwashableointment prepared from petrolatum, mineral oil, spermaceti and waterwith a surfactant such as sorbitan sesquioleate. The ingredients of saidointment are present in 10:10:6:68:6 parts by weight, respectively.

EXAMPLE 7

Lactic acid, USP grade 5 ml was dissolved in 10 ml of ice water andtriethanolamine, 4 ml was added to neutralize partially the acidity ofthe solution. This solution was admixed with 81 grams ofwater-nonwashable ointment prepared from petrolatum, mineral oil,isopropyl myristate, spermaceti and water with a surfactant such assorbitan sesquioleate. The ingredients of said ointment are present in10:10:10:6:58:6 parts by weight, respectively.

EXAMPLE 8

α-Hydroxyisobutyric acid, 5 grams and sorbitol 2 grams were dissolved in8 ml of water. This solution was admixed with 85 grams ofwater-nonwashable ointment prepared from petrolatum, mineral oil,spermaceti and water with a surfactant such as sorbitan sesquioleate.The ingredients of said ointment are present in 10:10:6:68:6 parts byweight, respectively.

EXAMPLE 9

Pyruvic acid 2 ml, glycolic acid 2 grams, citric acid 2 grams, andlactic acid 2 ml were dissolved in 12 ml of water. This solution wasadmixed with commercially available USP grade hydrophilic ointment (80grams) to a uniform consistency. A water-washable ointment thus preparedcontained four active ingredients.

TEST RESULTS

(A) Severe Dry Skin

Ten patients with severe dry skin conditions such as ichthyosis wereinstructed first to wet the body by taking a shower and then apply athin film of the compositions formulated according to Examples 4, 7 or 9on left side of the body. Other commercially available preparations suchas vegetable oil or petrolatum were applied on right side of the body.Twice daily topical application was continued for several weeks. In allthe patients tested the left side of the body became less flaky and feltsmoother than the right side after about a week of topical treatment.The rough and flaky lesions on the left side of the body weresubstantially clear after ten days of treatment. The left side of thebody devoid of any cracking, flaking or scaling usually reached animproved state comparable to normal appearing skin within two to threeweeks after initial treatment. Very little or no substantial improvementwas seen on the right side of the body, which had been treated withvegetable oil or petrolatum alone. Therefore after three weeks thepatients were instructed to apply the composition of the presentinvention on the right side of the body. Again, the skin on the rightside of the body became normal appearing within two to three weeks.

Once a normal appearing skin was restored, it remained improved for fromseveral weeks to several months, varying from patient to patient,without further application of the ointment. It was, however, necessaryto continue the application of the ointment in order to maintain theskin free from recurrence of the overt disease.

(B) Common Dry Skin

Human subjects with mild to moderate degrees of dry skin conditions, asevidenced by dry, cracking or flaking of the skin, were instructed toapply topically the lotion, cream or ointment of the present inventionformulated according to Examples 1 through 8 on the affected skin areas.Twice daily topical application was continued for a few weeks. In allthe twenty-three human subjects tested the feeling of the skin drynessdisappeared after three to four days of topical treatment. In twenty-onehuman subjects tested the rough and cracked skin usually became lesspronounced within a week time. Generally the skin appeared normal andfelt smooth after about two weeks of topical treatment.

In contrast to the severe dry skin disease the common dry skinconditions once restored to normal appearing skin remained improved forsome time until causes of dry skin, such as low humidity, cold weather,detergents, soaps, chemicals, etc., recurred. On continued use it wasalso found that twice daily topical application of a composition of thepresent invention prevented the development of new dry skin lesions.

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The presentembodiment is, therefore, to be considered in all respects asillustrative and not restrictive, the scope of the invention beingindicated by the appended claims rather than by the foregoingdescription, and all changes which come within the meaning and range ofequivalency of the claims are, therefore, intended to be embracedtherein.

What is claimed and desired to be secured by United States LettersPatent is:
 1. A non-irritating therapeutic composition for alleviatingthe symptoms of dry skin in humans comprising: a therapeuticallyeffective amount of a reaction product prepared by reacting, in aqueousor alcoholic aqueous solution at least one member selected from thegroup consisting of citric acid, glycolic acid, glucuronic acid,galacturonic acid, glucuronolactone, gluconolactone, α-hydroxybutyricacid, α-hydroxyisobutyric acid, mandelic acid, mucic acid, pyruvic acid,methyl pyruvate, ethyl pyruvate, β-phenyllactic acid, α-phenylpyruvicacid, saccharic acid, tartaric acid, tartronic acid, andβ-hydroxybutyric acid and a base selected from a group consisting ofammonium hydroxide, an organic primary, secondary, or tertiaryalkylamine, alkanolamine, diamine, dialkylamine, dialkanolamine,alkylalkanolamine, trialkylamine, trialkanol amine, dialky alkanolamine, or alkyl dialkanolamine wherein the alkyl or alkanol substituenthas from 1 to 8 carbon atoms in a pharmaceutically acceptable vehiclefor topical application selected from the group consisting of lotion,cream, and ointment.
 2. The composition of claim 1 wherein the productis present in a concentration of from 1 up to about 20 percent by volumeof the total composition.
 3. The composition of claim 1 wherein theproduct is present in a concentration of from 2 up to about 10 percentby volume of the total composition.
 4. The composition of claim 1wherein the product comprises a reaction product of a member selectedfrom the group consisting of citric acid, glycolic acid, glucuronicacid, galacturonic acid, glucuronolactone, gluconolactone,α-hydroxybutyric acid, α-hydroxyisobutyric acid, mandelic acid, mucicacid, pyruvic acid, methyl pyruvate, ethyl pyruvate, β-phenyllacticacid, β-phenylpyruvic acid, saccharic acid, tartaric acid, tartronicacid, and β-hydroxybutyric acid and a memeber selected from the groupconsisting of ammonium hydroxide, methylamine, ethylamine,monoethanolamine, monoisopropanolamine, ethylenediamine,1,2-diaminopropane, dimethylamine, diethylamine, diethanolamine,diisopropanolamine, N-methylethanolamine, N-ethylethanolamine,triethylamine, triethanolamine, N-methyldiethanolamine, andtriisopropylamine.
 5. The composition of claim 1 wherein the vehicle isat least one member selected from the group consisting of water,ethanol, and propylene glycol present therein in a concentration of upto 99, 70, and 30 percent, respectively.
 6. The composition of claim 1wherein the pH thereof is from 3.5 to about 7.5.
 7. The composition ofclaim 1 comprising: a reaction product of from about 5 to about 7 partsglycolic acid, and about 3 to about 5 parts ethanolamine in about 10parts water per 100 parts of said vehicle.
 8. The composition of claim 1comprising: a reaction product of about 5 parts glycolic acid and 3parts ethanolamine in a vehicle of mineral oil, cottonseed oil,isopropyl palmitate, water, and a surfactant present in a ratio of15:15:5:60:5 per 100 parts of said vehicle.
 9. The composition of claim1 comprising: a reaction product of 10 parts glycolic acid and 7 partsethanolamine in 20 parts cetyl alcohol, 5 parts polyoxyethylene (20)sorbitan monooleate, 45 parts water, and 10 parts propylene glycol. 10.The composition of claim 1 comprising: a reaction product of 7 partsglycolic acid and 5 parts ethanolamine in 10 parts water in a vehicle ofpetrolatum, mineral oil, spermaceti, water, and a surfactant present ina ratio of 10:10:6:68:6 parts per 100 parts of said vehicle.
 11. Amethod of alleviating the symptoms of dry skin in humans comprising:topically applying to involved areas of the body an effective amount ofa composition comprising: a therapeutically effective amount of amixture of members of the group selected from citric acid, glycolicacid, glucuronic acid, galacturonic acid, glucuronolactone,gluconolactone, α-hydroxybutyric acid, α-hydroxyisobutyric acid, lacticacid, malic acid, mandelic acid, mucic acid, pyruvic acid, methylpyruvate, ethyl pyruvate, β-phenyllactic acid, β-phenylpyruvic acid,saccharic acid, tartaric acid, tartronic acid, and β-hydroxybutyric acidin a pharmaceutically acceptable vehicle.
 12. The method of claim 11wherein the mixture is present in a concentration of from 1 up to about20 percent by volume of the total composition.
 13. The method of claim11 wherein the mixture is present in a concentration of from 2 up toabout 10 percent by volume of the total composition.
 14. The method ofclaim 11 wherein the composition comprises about 5 partsα-hydroxyisobutyric acid in 2 parts sorbitol and 8 parts water admixedwith 85 parts of a pharmaceutically acceptable vehicle.
 15. The methodof claim 11 wherein the composition comprises about 2 parts pyruvicacid, 2 parts glycolic acid, 2 parts citric acid, and 2 parts lacticacid in 12 parts water, admixed with 80 parts of said vehicle.